Neurobiology

Bruce P. Bean, Ph.D

Professor of Neurobiology

Each neuron in the brain possesses about 30 different types of ion channels, molecular pores in the membrane of the neuron. Most of these are closed when the neuron is at rest (electrically silent), and it is the coordinated, transient opening ("gating") of particular types of ion channels that underlies electrical signaling by the neuron. Dr. Bean and his associates are studying the molecular mechanisms of ion channel gating, especially the ways that channel gating can be modified by neurotransmitters and by drug molecules. Individual projects on different ion channels have in common a focus on understanding the precise kinetics of channel gating and use similar biophysical techniques. One set of projects studies voltage-dependent calcium channels, which are involved in many neuronal functions, including synaptic transmission between neurons. The gating of calcium channels is controlled by membrane voltage on a millisecond time scale, but channel gating can be modulated over a longer time (seconds to many minutes) by neurotransmitters like glutamate, GABA, and norepinephrine. One goal is to understand the cellular pathways by which this modulation occurs and the mo-lecular mechanisms by which channel gating is altered.

Cells of the central nervous system possess many different types of calcium channels, and another goal is to identify drugs or naturally occurring compounds that selectively target individual types of calcium channels. So far, the most potent and selective compounds have come from the venoms of poisonous spiders and snails. These agents can help clarify the functions of different types of calcium channels in normal neuronal function. In addition, excessive calcium entry through voltage-dependent calcium channels may contribute to neuronal death following a stroke, and drugs targeted to specific brain calcium channels may be clinically useful.

Another set of projects is focused on channels gated by GABA, one of the two major neurotransmitters in the brain. Some actions of GABA on ion channels are mediated by intermediary GTP-binding proteins. In hippocampal neurons, GABA both activates a class of inward rectifier potassium channels (members of the family being studied at the molecular level by John Adelman and associates) and inhibits voltage-dependent calcium channels. The researchers are trying to understand what is common to and what is different about the cellular pathways leading to these two effects.

Other effects of GABA are mediated by direct binding to chloride channels. This binding can be altered by a wide variety of common drugs, including alcohol, general anesthetics, and anti-anxiety agents, and the researchers are studying how the kinetics of channel gating and GABA binding are altered by these drugs. Other projects examine the role of particular ion channels in controlling the firing patterns of particular neurons in the brain and explore how firing patterns are modified during normal changes in brain activity or abnormal changes such as epilepsy. A major focus is on voltage-dependent sodium channels, which are an important target of anti-epileptic drugs.

Current through voltage-dependent calcium channels in a cerebellar Purkinje neuron. The channels are opened by a voltage change from -80 mV to -30 mV. Current flows into the cell when the channels are open. Applying baclofen, a drug that mimics the action of a naturally occurring neurotransmitter, produces a reversible reduction in the current. Application of w-Aga-IVA, a peptide that was purified from the venom of a poisonous spider, produces complete inhi-bition of the calcium channels. Other types of calcium channels in other parts of the brain are completely unaffected by this peptide. This and other peptides that inhibit calcium channels may be useful in treating stroke or intractable pain.